Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCZDXAL)

• DOT Name: DnaJ homolog subfamily C member 5 (DNAJC5)
• Synonyms: Ceroid-lipofuscinosis neuronal protein 4; Cysteine string protein; CSP
• Gene Name: DNAJC5
• Related Disease:
  Adult glioblastoma
  Alzheimer disease
  Ceroid lipofuscinosis, neuronal, 4 (Kufs type)
  Cleft lip/palate
  Cleft soft palate
  Depression
  Glioblastoma multiforme
  Malaria
  Movement disorder
  Multiple sclerosis
  Nervous system inflammation
  Obstructive sleep apnea
  Parkinsonian disorder
  Plasmodium vivax malaria
  Schizophrenia
  Wilson disease
  Adult neuronal ceroid lipofuscinosis
  Chronic obstructive pulmonary disease
  Pneumonia
  Tauopathy
• UniProt ID: DNJC5_HUMAN
• PDB ID: 2N04; 2N05
• Pfam ID: PF00226
• Sequence:
  MADQRQRSLSTSGESLYHVLGLDKNATSDDIKKSYRKLALKYHPDKNPDNPEAADKFKEI
  NNAHAILTDATKRNIYDKYGSLGLYVAEQFGEENVNTYFVLSSWWAKALFVFCGLLTCCY
  CCCCLCCCFNCCCGKCKPKAPEGEETEFYVSPEDLEAQLQSDEREATDTPIVIQPASATE
  TTQLTADSHPSYHTDGFN
• Function: Acts as a general chaperone in regulated exocytosis. Acts as a co-chaperone for the SNARE protein SNAP-25. Involved in the calcium-mediated control of a late stage of exocytosis. May have an important role in presynaptic function. May be involved in calcium-dependent neurotransmitter release at nerve endings.
• Tissue Specificity: Expressed in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain and heart.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  GABA synthesis, release, reuptake and degradation (R-HSA-888590)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Ceroid lipofuscinosis, neuronal, 4 (Kufs type)	DISC5V9S	Strong	Autosomal dominant	[3]
Cleft lip/palate	DIS14IG3	Strong	Biomarker	[4]
Cleft soft palate	DISCN11I	Strong	Genetic Variation	[4]
Depression	DIS3XJ69	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Malaria	DISQ9Y50	Strong	Biomarker	[6]
Movement disorder	DISOJJ2D	Strong	Biomarker	[7]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[8]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[8]
Obstructive sleep apnea	DIS0SVD1	Strong	Biomarker	[9]
Parkinsonian disorder	DISHGY45	Strong	Biomarker	[10]
Plasmodium vivax malaria	DISPU3H9	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[12]
Wilson disease	DISVS9H7	Strong	Biomarker	[13]
Adult neuronal ceroid lipofuscinosis	DIS5UHAA	Moderate	Autosomal dominant	[14]
Chronic obstructive pulmonary disease	DISQCIRF	Disputed	Biomarker	[15]
Pneumonia	DIS8EF3M	Disputed	Biomarker	[15]
Tauopathy	DISY2IPA	Limited	Genetic Variation	[16]

10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DnaJ homolog subfamily C member 5 (DNAJC5).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DnaJ homolog subfamily C member 5 (DNAJC5).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DnaJ homolog subfamily C member 5 (DNAJC5).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DnaJ homolog subfamily C member 5 (DNAJC5).	[21]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DnaJ homolog subfamily C member 5 (DNAJC5).	[21]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of DnaJ homolog subfamily C member 5 (DNAJC5).	[22]
Imipramine	DM2NUH3	Approved	Imipramine increases the expression of DnaJ homolog subfamily C member 5 (DNAJC5).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of DnaJ homolog subfamily C member 5 (DNAJC5).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DnaJ homolog subfamily C member 5 (DNAJC5).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DnaJ homolog subfamily C member 5 (DNAJC5).	[26]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of DnaJ homolog subfamily C member 5 (DNAJC5).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of DnaJ homolog subfamily C member 5 (DNAJC5).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of DnaJ homolog subfamily C member 5 (DNAJC5).	[24]

References

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• [2] Increased Expression of the Large Conductance, Calcium-Activated K+ (BK) Channel in Adult-Onset Neuronal Ceroid Lipofuscinosis.PLoS One. 2015 Apr 23;10(4):e0125205. doi: 10.1371/journal.pone.0125205. eCollection 2015.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] A Comparative Study of Oral Microbiota in Infants with Complete Cleft Lip and Palate or Cleft Soft Palate.Biomed Res Int. 2017;2017:1460243. doi: 10.1155/2017/1460243. Epub 2017 Mar 14.
• [5] Mechanism of Chaihu Shugan Powder () for Treating Depression Based on Network Pharmacology.Chin J Integr Med. 2020 Dec;26(12):921-928. doi: 10.1007/s11655-019-3172-x. Epub 2019 Sep 25.
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• [8] Immunomodulatory activity of polysaccharides isolated from Clerodendrum splendens: beneficial effects in experimental autoimmune encephalomyelitis.BMC Complement Altern Med. 2013 Jun 28;13:149. doi: 10.1186/1472-6882-13-149.
• [9] Associations Between Obstructive Sleep Apnea and Measures of Arterial Stiffness.J Clin Sleep Med. 2019 Feb 15;15(2):201-206. doi: 10.5664/jcsm.7616.
• [10] DNAJC proteins and pathways to parkinsonism.FEBS J. 2019 Aug;286(16):3080-3094. doi: 10.1111/febs.14936. Epub 2019 Jun 20.
• [11] Study of the genetic discrimination between imported and autochthonous cases of malaria in South Korea.J Travel Med. 2011 Jan-Feb;18(1):63-6. doi: 10.1111/j.1708-8305.2010.00473.x. Epub 2010 Dec 16.
• [12] Molecular evolution in the CREB1 signal pathway and a rare haplotype in CREB1 with genetic predisposition to schizophrenia.J Psychiatr Res. 2014 Oct;57:84-9. doi: 10.1016/j.jpsychires.2014.06.008. Epub 2014 Jun 24.
• [13] Different cortical excitability profiles in hereditary brain iron and copper accumulation.Neurol Sci. 2020 Mar;41(3):679-685. doi: 10.1007/s10072-019-04147-0. Epub 2019 Nov 26.
• [14] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [15] Identification of potential key genes associated with severe pneumonia using mRNA-seq.Exp Ther Med. 2018 Aug;16(2):758-766. doi: 10.3892/etm.2018.6262. Epub 2018 Jun 7.
• [16] Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator.EMBO Mol Med. 2018 Nov;10(11):e8587. doi: 10.15252/emmm.201708587.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [19] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [20] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [21] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [22] Induction of cysteine string protein after chronic antidepressant treatment in rat frontal cortex. Neurosci Lett. 2001 Apr 6;301(3):183-6. doi: 10.1016/s0304-3940(01)01638-x.
• [23] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [25] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.